Benzophenoxhiazine dyes and meth-



Patented Aug. 19, 1952 BENZOPHENOTHIAZINE DYES AND METH H 'ODS OFPREPARING THE SAME Richard C. Clapp, Old Greenwich, Conn., assignor toAmerican Cyanamid Company, New York, N. Y., a corporation of Maine NoDrawing. Application April 2, 1951, Serial No. 218,886

' 6 Claims.

This invention relates to new dyestuffs of the benzophenothiazineseries,- their addition salts with acids and methods of preparing thesame. When in the form of their free bases-the new compounds of thisinvention may be represented by the following structural formula: 1

in whichRi and R; are lowervalkyl radicals, for instance methyl, ethyland butyl, and R3 is an aryl group. The new 'phenothiazines may beisolated in the form'of their free bases or they may also be isolated inthe form of their addition salts with acids, for.instance as thehydrochloride or citrate. While several formulations for the acidsalts'have been proposed, it is believed that the following bestcorresponds with the known characteristics of the compounds:

extent of tumorous-;growth and the possible existence-50f metastasis,if. a dye has been previously administered to-the subject which dyes thetumor tissues to a greater extent than the normal bodytissue. Likewise,in making microscopic slides, dyes whichpreferentially stain oneparticular type-of tissue are of-value.

some of the new compoundsalso have therapeutic activity. For instance;the compound of the above formula in which R1 and R2 represent propylgroups and. R3; represents para-tolyl has shown considerable; activityagainst tubercle bacilliinfectionswin mice.- By-employingthis com-.pound in thezfeed given' mice infected with an x otherwise deadlytubercle bacilli infection, the life of the mice can be greatlyprolonged.

As stated above, R3 represents an aryl group. The aryl group ispreferably one having one or two homocyclic rings, for instance phenylor naphthyl. In many instances the substitution of the aryl radicalgives compounds having more desirable properties and it is intended thatcompounds having the aryl groups substituted by such substituents aslower alkyL-for instance methyl; and lower alkoxy, for instance ethoxy,be within the scope of this invention. Compounds having the aryl groupsubstituted by a negative group, for instance chloro, are also of value.

While it is not intended that this. invention be limited to the newdyestuffs produced in any particular manner, a convenient method ofpreparing the new compounds has been discovered and it is intended thatthis new method also constitute a part of the invention. The new methodcomprises reacting a 2-amino-5-dialkylaminobenzenethiosulfuric acid witha N-aryl-l-naphthylamine as illustrated by the following equation:

in which RI fRZ and R3 are as defined above.

The reaction is preferably performed in an inert solvent. Suitable inertsolvents may be illustrated by the following: water; lower fatty acids,for instance acetic acid; lower alcohols, for instance ethyl alcohol;and cyclic ethers, for instance dioxane. A preferred procedure involvesforming a solution of the two reactants and adding thereto 'or formingtherein a suitable strong oxidizing agent, for instance chromic acid.The reaction proceeds slowly at room temperature, for instance 20-30 C.and may be performed at such temperatures if desired; however, thereaction velocity is increased by higher temperatures and temperaturesfrom -110 C. are preferred. If desired, the reaction may be carried outat even higher temperatures, for instance C.

This invention will be more fully illustrated by the following specificexamples in which all parts are by weight unless otherwise indicated:

EXAMPLE I 9 diethylamino phenyZimino-benzola]pita nothiazine parts byvolume glacial acetic acid- 27 parts by volume 10% potassium dichromatein water The first four reagents were mixed, and the dichromate solutionwas added dropwise at room temperature in twelve minutes. The mixturedarkened rapidly and became blue-green. After stirring for twentyminutesv at room temperature; it wasstirred for two hours on the steambath. The mixture was then cooled and poured into water. A precipitatecould be formed from this solution by the addition of hydrochloric acidand salt, but the greater part was worked up as described below.

The diluted acetic acid solution was made basic with ammonia, andthe'flocculent precipitate was filtered, washed with water, and dried atC. The dried product was dried to a powder and extracted with two 100parts by volume portions of boiling benzene. The insoluble material wasdiscarded. The dark red benzene solution was shaken thoroughly with 10%hydrochloric acid. The liquid phases were drawn ofi carefully from thedark blue gummy material that adhered to the walls of the separatoryfunnel, and this residue was washed twice in situ with benzene and twicewith 10% hydrochloric acid. The gummy solid in the funnel was dissolvedin alcohol and the'solution concentrated in vacuo; The

residue was treat'ed with ammonium'hydroxide to give a solid product.greenish in hue but becoming red-brown on 'powdering; The productcrystallized from benzene-"hexane asdark green, glisteningfcrystals thatmelted 'from 235 C. to 24 C. It'appeared to be'chromatographicallypuire."

p v 1 Y EXAMPLE II 9 dipropylamino 5 11- tolyliminoben o [a]phenothiazine NH; 7 NH:

" (CaH'l)zN- ((.1e|EI1)2 I zOzH A. 2-AMINO-5-DI-PROPI1A'MINOBENZENETHIO-SULFURIC ACID Reagents: V

33.5 parts by weight p aminodipropylaniline 122 parts by weight aluminumsulfate (18H2O) in 440 parts by volume of water 62.5 parts by weightsodium thiosulfate in 330 parts by volume of water 23.8 parts by weightzinc chloride in parts by volume of water 14.5 parts by weight potassiumdichromate in 180 parts by volume of water To a mixture of thep-aminodipropylaniline and the aluminum sulfate solution, vigorouslystirred in an ice bath, were added the sodium thiosulfate solution andthe zinc chloride solution. The potassium dichromate solution was thenadded dropwise over a period of two hours. After stirring in the icebath for an additional hour, the solid was filtered and washed twicewith ice water. A 50-50 alcohol-ethersolution was also used to wash thesolid materialfrom the flask. A light purple product that melted anddecomposed from 193 C. was obtained. Five grams of this product wasdissolved in 500 parts by volume of alcohol. 'Aftertreatment with alittle Darco and concentration to about 200 parts by volume, colorless,finely-divided crystals that melted and decomposed from 208 C.

-- were obtained.

1;. 9-DIPROPYLAMFNOb-p-TOLYLIMINOBENZO [a] PHE'N'OT-HIAZI'NE Reagents:

14.9 parts by weight Z-amino-S-dipropylamlnobenzenethiosulfuric acid I r11.4 parts'by weight N-p-tolyl-l-naphthylamine 4.1 parts by volumeconcentrated hydrochloric acid. v Y l 375 parts by volume glacial aceticacid 184 parts by volume10% potassium dichromate in water.

The dichromate solution was added dropwise over thirty minutes to thestirred and cooled mixture of the otherreactants,which'rapidlybecamedark blue-green. Stirring was continued for one hourat room temperatureand then for four hours on the steam bath. After the reaction mixturehad stood at room-temperature for sixteen hours, it was poured into asolution of 600 parts by volume of concentrated ammonium hydroxide and750 parts by volume of water with cooling and stirring. The precipitatewas filtered, washed with water, and then extracted three times with 300parts by volume portions of boiling benzene and twice with parts by'volume portions; To the cold benzene solution was added 750 parts byvolume of 10% hydrochloric acid, and the mixture was thoroughly shakenin a flask. The dark blue, partially solid precipitate was filtered,washed with a little 10% hydrochloric acid and benzene, and dissolved in1 liter of alcohol. This alcoholic solution was treated dropwise withammonium hydroxide while stirring and cooling in ice, and water wassubsequently added to ensure complete precipitation of the free base.After thorough cooling, 15.1 parts by weight of a dark, purple-red solidthat melted from 145 to 160 C. was obtained. Crystallization of 9.7parts by weight of this material from 970 parts by volume of heptane(Darco) gave dark brown, finely-divided crystals (needles) melting pointI'M-176 C. However, crystallization of the remaining 5.4 parts by weightfrom 540 parts by volume of heptane (Darco) gave 3.26 parts by weight ofgreen crystals with a metallic lustre; melting point 197-199 C.Crystallization in the latter case probably took place more slowly.These two spectrally similar products appear to represent twocrystalline forms of the compound, and the lower melting form could beconverted to the higher melting form by crystallization from heptane andseeding with the latter. The compound appeared to be chromatographicallypure.

EXAMPLE III 9-dimethylamino-5-phenyliminobenzolal phenothiazine (CHahNSgOaH (CH3)2N S Reagents:

Two-thirds of the dichromate solution was added dropwise to a stirredand cooled mixture of the other reactants. The ice bath was thenremoved, and the remainder of the dichromate solution was added dropwiseat room temperature. The mixture was stirred on the steam bath for fourhours. The precipitate from the reaction mixture was filtered, and itwas then stirred with 120 par-ts by volume of concentrated ammoniumhydroxide and 480 parts by volume of water for forty minutes. Theresulting precipitate of the free base was extracted three times with200 parts by volume of boiling benzene. The benzene solution wasconcentrated to a smaller volume and was shaken with an equal volume ofhydrochloric acid. The blue precipitate that separated was dissolved in500 parts by volume of alcohol, and the alcoholic solution was madealkaline with ammonia and diluted with water. Crystallization of theresulting precipitate from benzene and petroleum ether gave a brownproduct melting from 244 to 249 C.

6 I claim: 1. The new compounds represented by the formula:

in which R1 and R2 represent lower alkyl radicals and R3 represents anaromatic nucleus having one to two G-membered homocyclic rings, and acidaddition salts thereof.

2. Compounds represented by the formula in which R1 and R2 representlower alkyl groups and R3 represents tolyl.

3. 9-dipropylamino 5 p-tolyliminobenzc[alphenothiazine.

4. Compounds represented by the formula:

in which R1 and R2 represent lower alkyl radicals and R3 represents anaromatic nucleus having one to tWo G-membered homocyclic rings, and acidaddition salts thereof, which comprises reacting a2-amino-5-dialkylaminobenzenethiosulfuric acid with an-aryl-l-naphthylamine in an inert solvent in th presence of a strongoxidizing agent.

RICHARD C. CLAPP.

REFERENCES CITED The following references are of record in the file ofthis patent:

FOREIGN PATENTS Number Country Date 5,268 Great Britain 1896 96,690Germany Feb. 25, 1898 OTHER REFERENCES Nietzki et al.: Beilstein(Handbuch, 4th ed.), vol. 2'7, p. 405 (1937).

1. THE NEW COMPOUNDS REPRESENTED BY THE FORMULA: